PROJECT SUMMARY Obsessive-Compulsive Disorder (OCD) is a disabling condition that affects 2 to 3% of Americans and is associated with substantial distress, high economic costs, and poor quality of life. Research has also shown that a substantial proportion of individuals seeking treatment for OCD fail to respond. Given the negative impact of OCD, there is growing recognition for comprehensive models of the etiology and development of OCD that can better inform treatment and prevention efforts. Recent evidence from research employing multiple levels of analysis has shown a strong relation between disgust proneness and OCD. However, much remains unknown about the nature and function of disgust in OCD. A better understanding of the neural substrates of disgust proneness in OCD may aid ongoing efforts to improve treatment outcome. Preliminary research from our lab suggests that symptoms of OCD may be characterized by heightened disgust learning and a resistance to disgust extinction. The proposed research is designed to expand on this preliminary work by taking an endophenotypic approach to better understanding the neural basis of disgust learning and extinction in OCD. Such an approach may not only provide clues to underlying candidate genes contributing to OCD, but this approach may also point the way to a better understanding of pathophysiological mechanisms that interact to confer risk. To investigate the neural correlates of disgust learning and extinction as an endophenotype in OCD, the proposed study will measure brain activation using functional magnetic resonance imaging (fMRI) during performance on a novel disgust conditioning task in 30 OCD patients, 30 of their unaffected first-degree relatives, and 30 unrelated matched controls. The specific aims will identify large-scale brain systems in which activation is associated with variation in disgust learning and extinction. Specifically, the investigation will examine the extent to which heightened disgust learning and a resistance to disgust extinction, occurring predominantly in patients and relatives, is associated with activation in the anterior insula. These aims are consistent with the Research Domain Criteria project (RDoC) recently launched by the NIHM and the findings have the potential to advance current understanding of the development of OCD above and beyond traditional approaches.